Professional Documents
Culture Documents
BOBHFNFOUPG)FQBUJUJT$BOE
)*7$PJOGFDUJPO
$MJOJDBM1SPUPDPMGPSUIF8)0&VSPQFBO3FHJPO
Contents
IV. Suggested minimum data to be collected at the clinical level ........................................... 257
In Europe, the prevalence of hepatitis C virus (HCV) infection in HIV-infected patients is particu-
larly high – and still rising, in contrast to the rest of the world. Yet only a minority of HCV/HIV-
coinfected patients are treated for their hepatitis. The compounding effect of coinfection makes the
care for these patients a major challenge.
In the pre-HAART era, the late consequences of HCV-related chronic liver disease in coinfected
individuals were overshadowed by AIDS mortality connected with severe immune deficiency. With
the development of HAART, morbidity and mortality among HIV-infected patients have decreased
significantly. The consequences of liver-related disease associated with chronic HCV infection are
now far more worrying. End-stage liver disease (ESLD) is now the predominant cause of death in
patients coinfected by HCV and HIV, as well as in hepatitis B virus (HBV)/HIV-coinfected patients
(1), despite the availability of treatments with proven efficacy (2–5). Most patients are, however,
not treated, underscoring the need for treatment guidelines. Efforts must also be made, via multidis-
ciplinary health-care services, to increase the applicability and availability of treatment, especially
in more vulnerable populations, including but not limited to migrants, injecting drug users (IDUs),
prisoners, people with psychiatric illnesses and people who consume too much alcohol.
North: 24.5 %
East: 47.7 %
Central: 22.9 %
South: 44.9 %
229
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
The prevalence of HCV antibodies also varies widely among HIV transmission groups, ranging
from 7–8% in men who have sex with men to 60–70% in haemophiliacs and 80–90% in IDUs, the
most important group (see Fig. 2) (8–12). HCV is easily transmitted among IDUs, which makes it
difficult to prevent. IDU transmission occurs in several ways:
• sharing needles and syringes
• sharing auxiliary paraphernalia, such as cookers, straws, swabs, tourniquets and cotton
• sharing drug doses from a common syringe
• accidental needle-sticks.
HCV
HBS ag
% Positive
The prevalence of HCV among IDUs increases with the duration of injection, as shown in Fig. 3.
HCV
HBS ag
230
Management of Hepatitis C and HIV Coinfection
1.3. Genotypes
HCV exhibits a high genetic heterogeneity around the world, with six different clades or genotypes
being distinguished and differing as much as 30% in their genome (see Fig. 4). Furthermore, phylo-
genetic analyses can also distinguish subtypes and isolates within a particular type.
HCV
From an epidemiological point of view, infection with genotypes 3 and 4 is more prevalent in IDUs
and HIV-coinfected patients than in monoinfected patients. Acute
HBS aggenotype 4 infection has recently
been found among MSM (16).
% Positive
The distribution of genotypes may differ from one region of the world to another. As genotypes
have differed in their sensitivity to the standard treatment since 2005 – pegylated interferon (PEG-
IFN) and ribavirin (RBV) – it is important to know the genotype of each patient and the distribution
of the genotypes in each country.
Fig. 5. Prevalence of genotypes 1–3 in the United States and western Europe
231
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
1
HCV RNA testing should, therefore, be performed in people at risk, such as IDUs and MSM, and in others who may be
profoundly immunosuppressed and present unexplained ALT elevation despite negative HCV serology.
232
Management of Hepatitis C and HIV Coinfection
Extended follow-up in various studies indicate that patients on HAART do not have any major dif-
ferences in HIV-related mortality from HCV/HIV-coinfected patients or those infected with HIV
alone, particularly if ART is given (6). There is, however, an increased risk for liver disease-related
morbidity and mortality in hepatitis-coinfected HIV, as well as more hepatotoxicity under ART
regimens (30).
233
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
1.1.1. Step 1: All HIV-infected patients should be tested for HCV antibodies.
• For patients with acute HCV infection, it is important to bear in mind that antibodies may not
be detectable for three to eight weeks following initial HCV infection. Retesting is not neces-
sary if the infection was transmitted heterosexually and in the absence of other risky behaviour.
For others who continue to run the risk of infection, such as active IDUs or MSM with multiple
partners, testing is recommended every one to two years (31).
• The presence of HCV antibodies is indicative of past or present infection. Antibodies persist
indefinitely, in chronically infected patients but the antibody titres may decrease (and even dis-
appear) in patients who clear HCV (either spontaneously or after antiviral treatment).
• HIV infection can impair antibody responses to HCV infection (27), so a second- or third- gen-
eration enzyme immunoassay (EIA) for HCV antibodies should be used in coinfected individuals.
• In HCV antibody-negative HIV patients with profound immunosuppression, HCV RNA deter-
mination is recommended when there are liver test abnormalities or clinical suspicion of liver
disease.
1.1.2. Step 2: When testing for HCV antibodies is positive, detection of HCV RNA should be performed
to confirm or exclude active replication.
• HCV RNA can be detected as soon as a few days after infection.
• HCV RNA can be detected by PCR (polymerase chain reaction) or by TMA (transcription-me-
diated amplification).
• Persistence of HCV RNA more than six months after initial infection confirms chronic hepatitis
C (27, 31).
• Determination of HCV RNA can be done through qualitative or quantitative assays.
° A qualitative assay is enough for diagnostic purposes.
° A quantitative assay (viral load) is important for assessment of patients who will receive
HCV treatment.
• High pretreatment HCV RNA levels are associated with lower rates of sustained virological
response (SVR); the cut-off is generally 800 000 copies/ml (IU/ml) (32). SVR rates may reach
60% in persons with either a genotype other than 1 or 4, or genotype 1 HCV infection with an
HCV RNA level ≤800 000 IU/ml after 48 weeks of PEG-IFN and RBV treatment, as opposed
to only 18% for those with genotype 1 and an HCV RNA level >800 000 IU/ml. (2–5, 32).
• It is important to consider that viral load is higher (0.5–1 log on average) in HCV/HIV-coin-
fected individuals than in those who are monoinfected. This may also account for higher HCV
transmission to children born to coinfected mothers. Therefore, assays with a wide dynamic
range may represent an advantage.
234
Management of Hepatitis C and HIV Coinfection
• Infections with more than one HCV genotype appear to be more often (>5%) in patients coin-
fected with HCV and HIV, particularly IDUs and haemophiliacs (29, 35).
• HCV genotype plays a predominant role as a predictor of SVR in HIV-infected patients, as it has
been found in all studies of people without HIV infection.
° For genotypes other than 1 or 4, SVR rates are generally high, ranging from 73% in the
ACTG 5071 study (4) to 62% in the APRICOT study (3), 53% in the Barcelona study (5) and
44% in the RIBAVIC study (2).
° For genotype 1, SVR rates range from 29% in APRICOT (3) to 17% in RIBAVIC (2) and
14% in ACTG 507 (4), while Barcelona reported a 38% SVR rate for those with genotype 1
or 4 (5).
For more information about laboratory assays for HCV, please see Annex 1.
2
Alanine aminotransferase (ALT) levels do not necessarily reflect the stage of fibrosis, especially in HCV/HIV-coinfected pa-
tients. A normal ALT level alone should not be grounds to defer treatment. A biopsy in this situation can help to make a more
informed decision. In the RIBAVIC study, baseline ALT >3 times the upper limit of normal was a predictor of higher SVR.
3
Asparate aminotransferase (AST) levels should be controlled when performing the initial complete hepatic evaluation to elimi-
nate other causes of hepatic disease; for example, in cases of alcoholic intoxication there may be an increase in AST and GGT.
235
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
Points
Clinical and biochemical parameters
1 2 3
<2 mg/dl 2–3 mg/dl >3 mg/dl
(<34 µmol/l) (34–50 µmol/l) (>50 µmol/l)
Bilirubin
1.2.4. Ultrasound
Ultrasound (Doppler if possible) examination of the liver can reveal:
• cirrhosis: dysmorphy of the liver
• steatosis: hyperechogenic liver
• possibly early HCC: nodular unique or, rarely, multiple lesions.
Biopsies must be performed by trained physicians, as significant complications may occur in 1/200
patients. They should be read by specialized anatomopathologists, as subtle differences may change
236
Management of Hepatitis C and HIV Coinfection
the classification of the severity of the disease. These limitations impede generalized biopsies for all
HCV-infected patients (see section II.1.2.7 below for clinical situations not requiring liver biopsy).
Activity and fibrosis are two major histological features of chronic hepatitis C that are included in
proposed classifications, such as Ishak, Metavir and Knodell, that allow improved consistency in
interpretation of hepatic fibrosis with a somewhat weaker reproducibility for hepatic inflammation
grade (37, 38). See Table 4.
Lobular necrosis
Activity score (A)
Absent (0) Moderate (1) Severe (2)
Absent (0) A0 A1 A2
Parcellar Minimal (1) A1 A1 A2
necrosis Moderate (2) A2 A2 A3
Severe (3) A3 A3 A3
Table 4a.
This system assesses histological lesions in chronic hepatitis C using two separate scores, one for
necroinflammatory grade (A for Activity) and another for the stage of fibrosis (F). The fibrosis
stage and inflammatory grade are correlated, but for approximately one third of patients there is
discordance. In lower grades of liver fibrosis (F0–F1), regardless of HCV genotype, treatment can
be deferred. See Table 4a.
Recently, alternatives to biopsies have become available for coinfected patients (39), including a
combination of biochemical tests indicating the degree of liver inflammation and fibrosis, such as
the Forns index which has been recently validated for HIV/HCV-coinfected patients (40), and an
elastometric method reflecting the degree of fibrosis (see Annex 2) (41, 42).
237
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
Given the limitations of biopsy and the faster progression of fibrosis in HCV/HIV patients, treat-
ment should still be offered when candidates for biopsy decline it or lack access to it.
238
Management of Hepatitis C and HIV Coinfection
4
For HBV and HAV please refer to Protocol 7, Management of hepatitis B and HIV coinfection.
5
See Protocol 4, Management of tuberculosis and HIV coinfection, and the European STD Guidelines (46).
6
It should be explained that because RBV is teratogenic and contraindicated during pregnancy, procreation should be avoid-
ed during treatment and six months after, and that due to higher levels of HCV viraemia in coinfected women, approximately
20% transmit HCV to their offspring, versus 7–8% in those monoinfected with hepatitis C (47).
239
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
1.4.1. Algorithm 1
This algorithm is preferred and focuses on genotyping.
Fig. 6. Algorithm 1
Genotyping
1 or 4 2 or 3
High Low
>800 000 ≤800 000
Liver biopsy or
Not available
non-invasive markersa
a
FibroScan (image technique), Fibro Test (serum fibromarkers)
240
Management of Hepatitis C and HIV Coinfection
In Algorithm 1, the decision to treat lies mainly upon the HCV genotype determination and HCV
quantification. Liver biopsy is limited to patients with genotype 1, high viral load and low response
to PEG-IFN and RBV.
• Subsequent to an HCV/HIV positive serology, qualitative HCV RNA detection should be under-
taken to confirm the chronicity of hepatitis.
• In case of positive HCV RNA, a genotyping should be performed.
• In case of genotype 2 or 3, more frequently found in IDUs, treatment should be proposed for all
patients without liver biopsy where there is no contraindication (please see contraindications in
section III.2.3).
• In case of genotype 1, the patient should have a quantification of HCV RNA, since responses
are related to viral load. This test should be available everywhere HIV viral load is performed.
• In the absence of local testing possibilities, the patient should be referred to a specialist, or a
sample should be collected at the district level and a genotyping test done centrally.
° When viral load is low (≤800 000 IU/ml), treatment of genotype 1 is recommended without
a liver biopsy.
° When viral load is high (>800 000 IU/ml), an assessment of liver fibrosis by biopsy is rec-
ommended to differentiate patients with severe liver disease.
• A fibrosis score of F2–F4 indicates a need for immediate treatment.
• Mild liver disease (F0, F1) indicates that treatment should be delayed due to the low chances of
SVR.
• Follow-up treatment should rely on HCV RNA quantification at week 12, and then HCV RNA
qualitative detection at weeks 24 and 48.
° At week 12, if the drop of viral load is less than 2 log, the treatment should be stopped be-
cause the chance of success does not exceed 1–2% regardless of genotype. Otherwise, the
treatment should be continued.
° Additional qualitative tests should be performed at week 24 and treatment should be stopped
if HCV viral load is detectable; otherwise, treatment should be pursued until week 48 and
treatment efficacy checked with a qualitative test at this time.
° At week 72, HCV RNA detection should confirm or disprove a sustained virological re-
sponse.
• Patients with cirrhosis should also be referred to a specialist for initial evaluation of their cir-
rhosis.
241
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
1.4.2. Algorithm 2
This algorithm is an alternative, focusing on liver biopsy and other tools in the absence of
genotyping.
Fig. 7. Algorithm 2
Child-Pugh B or
HCV RNA + (qualitative or
decompensated
quantitative)
cirrhosis
Liver biopsy or
Mild
non-invasive markersa
Observe
Moderate-severe
Evidence of
clinical & lab
progression Treatment for
12 weeks
HCV RNA
(quantitative)
>2 log
drop or <2 log
negative drop
a
FibroScan (image technique), Fibro Test (serum fibromarkers).
242
Management of Hepatitis C and HIV Coinfection
Pre-
Initial
Tests therapeutic
evaluation
evaluation
HCV disease - qualitative HCV RNA +
- transaminases (ALT, AST), GGT, alkaline phosphatases, +
bilirubin, albumin, prothrombintime
- HCV genotype +
- quantitative HCV RNA +
- ultrasound examination of the liver +
- histological evaluation, non-invasive markers +
HIV a
- CD4 cell count +
- HIV RNA +
- present antiretroviral regimen +
Comorbidities and - HBV serology +
co-conditions - HAV serology +
- TB diagnosis +
- TSH dosage +
- auto-antibodies +
- creatininaemia, proteinuria +
- glycaemia +
- ferritinaemia +
- quantification of alcohol consumption +
- drug consumption +
- pregnancy test +
- ECG (if >50 years old or known cardiopathy) +
- psychiatric consultation if previous psychiatric history +
a
For more information refer to section on initial patient evaluation in Protocol 1, Patient evaluation and antiretroviral treat-
ment for adults and adolescents.
243
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
The key issue in the clinical management of HCV/HIV-coinfected patients is the treatment decision
for each condition and when to initiate it. By the end of the laboratory and clinical assessment of
patients with HCV/HIV coinfection, patients can be split into four categories:
1. patients not requiring hepatitis C or HIV/AIDS treatment
2. patients requiring only hepatitis C treatment
3. patients requiring only HIV/AIDS treatment
4. patients requiring both hepatitis C and HIV/AIDS treatment.
HCV treatment offers the possibility of eradicating HCV within a defined treatment period. In the
following situations, where the benefits outweigh the risks, there are two main reasons to consider
all HCV/HIV-coinfected patients for HCV treatment:
• The liver disease progresses more rapidly to end-stage complications and at earlier ages than in
HCV-monoinfected patients.
• Patients are at higher risk for developing hepatotoxicity following the initiation of ART than
HIV-monoinfected patients. Efficient HCV treatment will hence facilitate the subsequent man-
agement of ART.
7
Some patients may have HCV RNA but harbour genotype 1 or 4 and a mild disease. In such cases, treatment is not recom-
mended; regular yearly monitoring is the recommended option, with an assessment for liver fibrosis after three years.
8
For patients with evidence of advanced liver fibrosis, HCV treatment should be a priority.
244
Management of Hepatitis C and HIV Coinfection
The dose of RBV is critical. Although clinical trials in HIV/HCV-coinfected patients have used
a fixed dose of 800 mg per day [400 mg twice daily (BID)] for all genotypes, studies from HCV-
monoinfected patients support the use of 1000 mg to 1200 mg RBV per day (in 2 doses) for treat-
ment of infections with genotypes 1 and 4, and 800 mg RBV per day (400 mg BID) for genotypes
2 and 3 (49).
9
Limited data suggest IFN does not have any effect on the embryo or foetus.
10
RBV is teratogenic (causes birth defects) in multiple animal species and its use during pregnancy is contraindicated (48).
Since RBV may cause abnormalities in sperm, men taking it should wait six months after discontinuing use before attempting
to impregnate a woman.
11
IFN is very badly tolerated in these patients (49); however, after regression of the decompensation, treatment may sometimes
be initiated (50) and liver transplantation should be the primary treatment option for such patients.
245
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
Genotype 2 or 3 Genotype 1 or 4
Genotype 2 and 3 patients treated for six months have significantly higher relapse rates than those
treated for one year (5, 53). Therefore, all HCV/HIV-coinfected patients should be treated for one
year. HCV genotype can be used as a predictor of response but not as a basis for modifying treat-
ment duration, as with immunocompetent patients.
246
Management of Hepatitis C and HIV Coinfection
247
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
12
For patients with evidence of advanced liver fibrosis, HCV treatment should be a priority.
248
Management of Hepatitis C and HIV Coinfection
• In some cases (if CD4 nadir has never been <200 cells/mm3), interruption of HAART during
HCV treatment is feasible if the patient asks for it. In this case, the original regimen is usually
reintroduced after the end of HCV treatment or in case the CD4 count drops <200 cells/mm3
during the treatment.
• Patients with a low baseline CD4 count (<200 cells/mm3) may tolerate HCV treatment less well
and may be at higher risk for developing opportunistic infections, since IFN treatment is often
associated with loss of CD4 cells in the bloodstream, although the CD4 percentage is conserved
(2–5).
ARV-treated It is possible to interrupt HAART until Treat HCV if CD4 > 200 cells/mm3.
the end of HCV treatment (if CD4 nadir
was never <200 cells/mm3, and patient
asks for it).
4.2. Considerations of ARVs when treating both HCV and HIV infections
249
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
Hepatotoxicity has been associated with all currently used ARV drugs, but existing studies fail to
demonstrate a consistent association between particular drugs or drug classes and the development
of subsequent hepatotoxicity. Comparison of HAART regimens (single-PI, multiple-PI and NNRTI-
based) has given inconsistent results for liver-tolerability in cohorts in which HCV/HIV-coinfected
patients are underrepresented.
• Acute hepatotoxicity: in a single cohort study involving HCV positive and negative patients, the
use of NVF within 12 weeks of initiating treatment and the use of full-dose ritonavir (RTV) (600
mg BID) have been implicated (62). But most liver enzyme elevation events are sub-clinical and
usually reverse spontaneously. NVP is not contraindicated in all HCV/HIV-coinfected subjects,
but should be closely monitored when used in asymptomatic patients. A majority of experts
recommend avoiding its use in patients with evidence of liver dysfunction.
• Chronic hepatotoxicity: the prolonged use of nucleoside analogue reverse transcriptase inhibi-
tors (especially of those having a strong affinity for mitochondrial deoxyribonucleic acid (DNA)
polymerase, such as ddI and d4T) exposes treated patients to a risk of chronic mitochondrial
toxicity, whose target, among other organs, is the liver. This toxicity, possibly exacerbated in
some patients by the specific chronic toxicity of PIs on the liver, may lead to hepatic steatosis
and worsen pre-existing fibrosis.
250
Management of Hepatitis C and HIV Coinfection
Table 10. Recommendations for antiretroviral dosage adjustment in patients with ESLD
4.4.1 Recommendations
• In the absence of specific recommendations, the full dose of ARVs is usually prescribed in
patients with compensated cirrhosis.
• If therapeutic drug monitoring is available, residual drug concentrations of ARVs should be
measured at the first monitoring visit in order to adjust dosages.
• In cases of decompensated cirrhosis where drug monitoring is not available, one should:
° avoid NNRTIs
° reduce the daily dosage of ZDV and ABC
° reduce the daily dose of most PIs (precise data are lacking).
251
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
5. Clinical monitoring
HCV/HIV coinfected patients should be carefully monitored during treatment. For monitoring of
patients receiving ART please refer to Protocol 1, Patient evaluation and antiretroviral treatment
for adults and adolescents.
Patients treated for HCV should be followed monthly for clinical evaluation of treatment tolerance.
The tests to be regularly performed are shown in Table 11.
Before W4 W8 W12 W16 W20 W24 W28 W32 W34 W36 W48 W72
treat-
ment
Blood count W1
W2
Tolerance
and X X X X X X X X X X X
platelets* W4
CD4 X X X X X X X X X
TSH X X X
Quantitative
HCV viral X X
Efficacy
load
Qualitative
HCV RNA X X X
Note: W=week
* Blood and platelets counts should also occur during weeks 1 and 2.
The log rule at week 12 in coinfected patients is of great relevance to optimizing treatment. It
encourages treatment of all candidates in the absence of contraindication, given that treatment can
be stopped after 12 weeks if there is no chance of a cure.
After week 12, assessment should be made by a qualitative HCV RNA test, as follows:
• Week 24: for patients remaining positive for serum HCV RNA at week 24 (negative predictive
value for achieving SVR is 100%), treatment should be discontinued.
• Week 48 marks the end of treatment response.
• Week 72: after six months off treatment, negative HCV RNA indicates an SVR. Recurrence of
HCV infection thereafter is very rare.
• A new assessment might also be useful 12–24 months after the end of treatment.
252
Management of Hepatitis C and HIV Coinfection
• RBV should be reduced to 600 mg/daily (200 mg in the morning and 400 mg in the evening) if
either of the following applies:
° the haemoglobin of a patient without significant cardiovascular disease falls to <10 g/dl and
≥8.5 g/dl; or
° the haemoglobin of a patient with stable cardiovascular disease fall by ≥2 g/dl during any
four weeks of treatment (a return to the original dosage is not recommended).
• RBV should be discontinued if either of the following applies.
° The haemoglobin of a patient without significant cardiovascular disease falls to <8.5 g/dl.
° A patient with stable cardiovascular disease maintains a haemoglobin value <12 g/dl despite
four weeks on a reduced dose.
253
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
If the abnormality is reversed, RBV may be restarted at 600 mg daily, and be increased to 800
mg daily at the discretion of the treating physician (a return to the original dosage is not recom-
mended).
• In case of RBV intolerance, PEG-IFN monotreatment should be continued.
• Dose reduction of PEG-IFN is recommended if the neutrophil count is <750/mm3 as described
in Table 12 (53). For patients with an absolute neutrophil count <500/mm3 treatment should be
suspended until values return to >1000/mm3. Treatment should be reinstituted at 50% of the
dose and the neutrophil count monitored.
• A 50% dose reduction is recommended if the platelet count is <50 000/mm3. Cessation of treat-
ment is recommended when platelet count decreases to levels <25 000/mm3.
5.4.4. Nausea
Nausea can be reduced with metoclopramide 10 mg three times daily (TID).
5.4.5. Depression
• Depressive mood changes are frequent and should be managed proactively with symptomatic
treatment. In patients with a history of neurotic or minor depression, initiation of treatment with
antidepressants before starting IFN-based treatment should be considered. Antidepressants are
frequently needed for clinically-relevant depression. Use the following dosages:
° selective serotonin reuptake inhibitors such as citaprolamin, paroxetin and tricyclic at initial
dosages of 20 mg/day; and
° antidepressants such as doxepine at an initial dosage of 50 mg/day.
• Consultation with an experienced psychiatrist for the establishment of a standardized treatment
procedure is recommended.
• In patients with pre-existing depressive mood disorders or other profound neurotic disorders,
initiation of specific psychiatric medication is recommended to reduce the destabilizing effect
of IFN-based treatment.
• In patients with a history of hospitalization due to major depression or psychosis, IFN-based
treatment is generally contraindicated. In large controlled studies the incidence of attempted or
completed suicides, psychosis and major depression is <1% (2–5, 71). The choice of treatment
strategy should be made in consultation with a psychiatrist.
• In patients with a history of injecting drug use, benzodiazepines should be avoided because of
their potential to induce addiction.
5.4.6. Dysthyroidism
IFN-induced dysthyroidism occurs in 7% of patients, but does not require treatment interruption.
• Thyroid hormone substitution is used in case of hypothyroidism.
• Beta-blockers are useful to relieve symptoms of hyperthyroidism (75).
254
Management of Hepatitis C and HIV Coinfection
work if necessary, with possible working time adjustments to accommodate for treatment and drug
reactions.
A team approach to patient care and management is an effective strategy for increasing adherence.
The team should include physicians, nurses, psychiatrists where relevant and social workers or
other care providers.
Initiatives that have proven effective include directly observed treatment, patient discussion groups,
patient manuals, hotlines and psychological support. For further information on adherence please
refer to Protocol 5, HIV/AIDS treatment and care for injecting drug users, and Protocol 1, Patient
evaluation and antiretroviral treatment for adults and adolescents.
If the therapeutic aim in treating patients with biopsy-proven advanced fibrosis/cirrhosis is to delay
or prevent disease progression in non-responders at week 12 and/or week 24, continuation with
PEG-IFN monotreatment can be considered, since a histological response was observed in about
35% of non-responders who received PEG-IFN + RBV in four pivotal trials (2–5). However, data
on dose, duration and clinical benefits of such maintenance treatment are very scarce in HCV/HIV-
coinfected patients, and further research is needed.
13
For further details on ESLD, please see Annex 4.
255
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
5.8.2. Interactions among recreational drugs, OST, anti-HCV drugs and ARVs
• No finding of interaction between opioids and anti-HCV drugs has been published.
• All PIs and NNRTIs are substrates and potent inhibitors or inducers of the cytochrome P450 sys-
tem. Many classes of recreational drugs, including benzodiazepines, amphetamines and opioids,
are also metabolized by the liver and can potentially interact with antiretrovirals. Overdoses as a
secondary reaction to interactions between the amphetamine-type stimulants (MDMA) and PIs,
particularly RTV, have been reported.
• ARVs that are CYP3A4 inducers (NVP, EFV and PIs) can decrease the level of methadone,
causing withdrawal symptoms and increasing the risk of relapse into heroin abuse.
• An opiate metabolism can be inhibited or induced by concomitant PIs, so patients should be
monitored for signs of toxicity. Withdrawal symptoms generally occur within 4–10 days of ART
initiation. Withdrawals should be monitored clinically and dose increases of 10 mg increments
from days 8–10 should manage the problem.
256
Management of Hepatitis C and HIV Coinfection
The following data should be collected at each clinical facility on a regular basis (e.g. monthly,
quarterly or semi-annually):
• number of HIV patients (“seen for care” – this will be the denominator for the data below);
• number of HIV patients coinfected with HCV;
• number of HCV/HIV-coinfected patients with chronic hepatitis C;
• number of HCV/HIV-coinfected patients with chronic hepatitis C receiving:
° only HCV treatment
° only ART
° both treatments; and
• number of HCV/HIV-coinfected patients who have died (in a given period) including cause of
death (e.g. liver-related deaths, HIV/AIDS related mortality or non-HIV/AIDS related mortality
such as accident, overdose or suicide).
257
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
The presence of HCV antibodies is indicative of past or present infection. Antibodies persist indefinitely
in chronically infected patients, but antibody titres may decrease or even disappear in patients who clear
HCV either spontaneously or after ART.
Different types of assays and immunoblot tests, were used in the past to confirm positive EIAs results
in low-risk populations, such as in healthy blood donors. The excellent performance of currently avail-
able EIAs and the general availability of HCV RNA testing make these assays outdated. In blood banks,
nucleic acid testing (NAT) has recently been implemented. With NAT, the presence of HCV RNA is
analyzed in small blood pools and, if a viral genome is detected, an individual analysis of the implicated
blood samples is performed. With the addition of NAT, the risk of HCV transmission has been reduced
to around 1/1 000 000 donations.
The qualitative detection procedure begins with RNA extraction from clinical samples. In most centres
RNA extraction has become fully automated, increasing its reproducibility. Thereafter, the target is am-
plified, either by PCR or TMA.
There are currently two commercially available qualitative assays to detect HCV RNA: one PCR-based
assay (Cobas Amplicor HCV v. 2.0, Roche) with a sensitivity of 50 IU/ml and one TMA assay (Versant
HCV RNA qualitative assay, Bayer) with a sensitivity of 5–10 IU/ml. The specificity of both assays is
close to 100%.
1. PCR assays
Quantification is based on amplification of the viral template with a known amount of synthetic RNA
standard added to each reaction. The relative amounts of amplified viral template and standard ampli-
cons are measured at the end of the PCR reaction. More recently, “real time” PCR has been developed,
with many advantages such as simplicity, rapidity, wider linear range of HCV RNA concentrations and
minor risk of contamination. Real-time PCR is already replacing conventional PCR assays.
2. DNA assay
Another approach to quantifying HCV RNA is signal amplification, in which viral genomes are released
from the virions and hybridized in solution using target probes. The HCV RNA with target probes are
258
Management of Hepatitis C and HIV Coinfection
then captured onto microwell plates. Additional target probes bind the viral RNA to branched-DNA
amplifier molecules. The signal is amplified by hybridization of oligonucleotide probes conjugated with
alkaline phosphatase for detection and quantification of the HCV RNA.
2. Serology: determination of HCV genotype can also be performed by detecting type-specific anti-
bodies. Several antigenic determinants have been identified after epitope mapping of the NS4 and core
proteins of HCV. These epitopes have been used to develop a competitive EIA (Murex HCV EIA) and
an immunoblot assay (RIBA, Chiron Corp).
There are studies demonstrating a lower performance of tests aimed at detecting HCV antibodies in
HIV-infected patients, as well as cases of HCV antibody seroconversion coinciding with the administra-
tion of HAART (probably due to immune restoration). However, latest generation HCV antibody EIAs
have incorporated multiple HCV antigens and are very sensitive in HIV-infected patients. Recently,
sera from 559 HIV-infected and 944 HIV-negative IDUs were tested both for HCV antibodies using a
third-generation assay and for HCV RNA using a commercially available test. Of the HIV-infected indi-
viduals, 547 (97.8%) had detectable HCV antibodies, and only one HCV antibody-negative patient had
detectable HCV RNA (27, 28). The figure was similar for HIV-negative patients, indicating that HCV
antibody screening using latest generation assays is reliable in coinfected patients.
259
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
260
Management of Hepatitis C and HIV Coinfection
CAGE Test
CAGE (100) is an acronym of the four questions:
1. Have you ever felt you ought to Cut down on your drinking? (yes/no)
2. Have people Annoyed you by criticizing your drinking? (yes/no)
3. Have you ever felt bad or Guilty about your drinking? (yes/no)
4. Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (Eye-
opener)? (yes/no)
Item responses are scored 0 or 1, with a higher score an indication of alcohol problems. A total score of 2 or
greater is considered clinically significant.
AUDIT Test
The AUDIT Test (101) was developed as a simple method of screening for excessive drinking, alcohol de-
pendence and harmful drinking (see Table 14 below). It has the following advantages:
• cross-national standardization, the only screening test designed for international use;
• identifies hazardous and harmful alcohol use, as well as possible dependence;
• it is brief, rapid and flexible;
• designed for primary health-care workers; and
• focuses on recent alcohol use.
A score of 8 in men and 7 in women indicates a strong likelihood of hazardous or harmful alcohol consump-
tion. A score of 13 or more is suggestive of alcohol-related harm.
261
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
(0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost
4. How often during the past year have you found that you were not able to stop drinking once you had started?
(0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost
5. How often during the past year have you failed to do what was normally expected of you because of drinking?
(0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost
6. How often during the past year have you needed a first drink in the morning to get yourself going after a heavy drinking
session?
(0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost
7. How often during the past year have you had a feeling of guilt or remorse after drinking?
(0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost
8. How often during the past year have you been unable to remember what happened the night before because you had
been drinking?
(0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost
9. Have you or has someone else been injured as a result of your drinking?
(0) No (2) Yes, but not in the past year (4) Yes, during the past year
10. Has a relative or friend or a doctor or other health worker been concerned about your drinking or suggested you cut
down?
(0) No (2) Yes, but not in the past year (4) Yes, during the past year
262
Management of Hepatitis C and HIV Coinfection
Early diagnosis of HCC is particularly important in patients coinfected with HCV and HIV, because it
is more aggressive and, in its advanced stages, incurable (59). Prevention, therefore, becomes key to
controlling the health-care burden of this disease.
The recommendations for HCC management developed in 2000 by the European Association for the
Study of the Liver (EASL) (105) are being updated. Such recommendations might be problematic in
view of the wide geographical variations in disease epidemiology and treatment availability. Guidelines
for managing HCC arising in connection with HIV coinfection are lacking.
Early diagnosis
The 2000 EASL guidelines describe patient selection and surveillance intervals (105). Patients with cir-
rhosis should be screened, if liver transplantation is feasible. A screening interval of every six months
has been established to allow detection of tumours <3 cm in diameter. Patients whose screening results
are abnormal should be followed up at referral centres for diagnosis and staging.
Ultrasonography and measurement of alpha-fetoprotein (AFP) levels, at six-month intervals, are the
most commonly used methods to screen patients with cirrhosis for HCC (77, 106). AFP values >400
ng/ml are considered diagnostic of HCC.
Treatment
Treatment for HCC is usually classified as curative or palliative (77, 105). Curative treatment
includes:
• surgical resection
• liver transplantation
• arterial embolization
• percutaneous ethanol injection in patients with small tumours who are not candidates for resec-
tion; a modest survival advantage has been shown for chemoembolization in randomized, con-
trolled trials and one meta-analysis.
Most patients cannot undergo resection or liver transplantation because of underlying cirrhosis or
advanced disease at diagnosis.
Early-stage HCC
A solitary tumour <5 cm, or up to 3 tumours <3 cm, in a patient with well-preserved liver function,
constitutes early-stage HCC (4, 8). Monoinfected patients can be successfully treated with curative
therapies, although response rates and survival benefits are variable. Surgical resection and trans-
plantation yield 5-year survival rates ranging from 60% to 70%. Recurrence, however, can be as
high as 50% at 3 years and 70% at 5 years.
Percutaneous ethanol injection induces a complete response in about 80% of patients whose
tumours are ≤3 cm. Response rates are lower with large or multinodal tumours (105).
263
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
Advanced HCC
Most patients with HCC (approximately 50%) have advanced disease at diagnosis (77, 105). Pa-
tients with advanced disease are candidates for loco-regional or systemic treatments rather than
curative approaches (4). Transarterial chemoembolization is the only palliative therapy that has
been shown to improve survival, with careful patient selection.
As the survival of HIV-infected patients with ESLD is shorter than that of non-HIV-infected pa-
tients, the OLT evaluation should be done after the first liver decompensation. The current selection
criteria for HIV-positive transplant candidates include:
• no history of opportunistic infections or HIV-related neoplasms, except infections that can be
efficaciously treated and prevented, such as TB, candidiasis or Pneumocystis jirovecii pneumo-
nia (PCP);
• CD4 cell count >100 cells/mm3; and
• plasma HIV viral load suppressible with antiretroviral treatment.
For drug users, a two-year abstinence from heroin and cocaine is also required, although patients in
a methadone programme can be accepted.
The main problems in the post-transplant period are pharmacokinetic and pharmacodynamic in-
teractions between ARVs and immunosuppressors, and the management of HCV infection relapse,
one of the main causes of post-transplant mortality. Experience with PEG-IFN and RBV is scarce
in this population.
Table 15. Three-year survival of patients with and without HIV-infection who had a
liver transplant before and during the HAART period
Before HAART During HAART period
(<1996) (1996–2004)
Survival
HIV-infected patients HIV-infected patients Non-HIV-infected patients
(n = 32) (n = 24) (UNOS) (n = 5225)
One year 69% 87% 87%
Two years 56% 73% 82%
Three years 44% 73% 79%
264
Management of Hepatitis C and HIV Coinfection
HIV management
Studies addressing the optimal time in the course of chronic HIV infection to commence ART in
HCV-coinfected patients should be initiated.
Treatment duration
A shorter duration of treatment for patients with HCV genotypes 2 and 3 should be investigated.
In HIV-negative patients, SVR rates are the same for genotype 2 and 3 HCV infections if they are
treated for 24 weeks instead of 48. However, analogous studies have not been reported for PLHIV
(5). Thus, studies emphasizing alternative dosing intervals are also needed for genotype 2 and 3
HCV infection before shorter regimens can be recommended. On the other hand, it might be useful
to evaluate the usefulness of longer treatment duration for genotype 1 HCV infections with high
viral loads.
265
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
New treatments
As the current therapies are suboptimal in efficacy, tolerability and quality of life, the development
of new drugs to improve these issues should be actively pursued.
Phase II and III trials of new drugs should be performed in HIV/HCV-coinfected patients as a prior-
ity due to the accelerated course of hepatitis infections in these populations.
There are many compounds under development, and some have progressed into Phase II clinical
studies (111):
• Viramidine (Valeant) is a prodrug of RBV that causes substantially less anaemia. In phase II
studies, it was associated with less anaemia than RBV and SVR rates that were not inferior.
Phase III studies are underway.
• Albuferon-alfa™ (Human Genome Sciences), is a fusion of albumin and IFN that prolongs IFN
half-life.
• Interleukine-2 (IL-2) treatment has also been examined as a method to boost HCV antibody im-
mune responses and enhance treatment responses. However, an early study in HIV/HCV-coin-
fected patients was associated with significant toxicity and provided no evidence of effective-
ness (10).
• NM283 (Idenix) interferes with the HCV polymerase and, in Phase II studies; its use was associ-
ated with a modest reduction in HCV RNA levels.
• VX 950 (Vertex) is an HCV protease inhibitor that is being examined in clinical trials.
The development of direct antivirals that block essential viral enzymes represents a straightfor-
ward approach to developing new agents to target HCV. Although all HCV enzymes are, in theory,
equally appropriate for therapeutic intervention, the NS3–4A serine protease and the NS5B RNA
polymerase have emerged as the most popular targets. A number of competitive inhibitors of the
NS3 protease as well as nucleoside and non-nucleoside inhibitors of the NS5B polymerase are be-
ing developed. The efficacy shown by NS3 serine protease and the NS5B RNA-dependent RNA
polymerase inhibitors in recent proof-of-concept clinical trials has validated the effort of finding
clinical candidates and triggered a renewed interest in this area (112).
266
Management of Hepatitis C and HIV Coinfection
267
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
References
1. Salmon-Ceron D et al. Liver disease as a major cause of death among HIV-infected patients: roles of
hepatitis C and B viruses and alcohol. Journal of Hepatology, 2005, 42: 799–805.
2. Carrat F et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic
hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA, 2004, 292:2839–2848.
3. Torriani FJ et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-in-
fected patients. The New England Journal of Medicine, 2004, 351:438–450.
4. Chung RT et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic
hepatitis C in HIV-coinfected persons. The New England Journal of Medicine, 2004, 351:451–459.
5. Laguno M et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for
treatment of HIV/HCV coinfected patients. AIDS, 2004, 18:F27–F36.
6. Rockstroh JK et al. Influence of hepatitis C virus infection on HIV-1 disease progression and response
to highly active antiretroviral therapy. Journal of Infectious Diseases, 2005, 15, 192(6):992–1002.
7. Rockstroh JK et al. F12/4: influence of hepatitis C coinfection on HIV disease progression within the
EUROSIDA Cohort. Ninth European AIDS Conference (EACS): 1st EACS Resistance and Pharmacol-
ogy Workshop, Warsaw, 25–29 October 2003.
8. Sherman KE et al. Prevalence of antibodies to hepatitis C virus in patients infected with the human im-
munodeficiency virus. Journal of Infectious Diseases, 1991, 163:414–415.
9. Salmon-Céron et al. Hospitalized HIV-HCV coinfected patients. A French national survey made in June
2001. Médecine et maladies infectieuses, 2003, 33:78–83.
10. Saillour F et al. Prevalence and determinants of antibodies to hepatitis C virus and mark-
ers for hepatitis B virus infection in patients with HIV infection in Aquitaine. BMJ, 1996, 313:
461–464.
11. Hayashi PH et al. Prevalence of hepatitis C virus antibodies among patients infected with
human immunodeficiency virus. Journal of Medical Virology, 1991, 33: 177–180.
12. Sulkowski MS, Thomas DL. Hepatitis C in the HIV-infected patient. Clinical Liver Disease, 2003,
7(1):179–194.
13. Alter MJ. Epidemiology of viral hepatitis. Journal of Hepatology, 2006, 44(S1):S6–S9.
14. Quaglio GL et al. Hepatitis C virus infection: prevalence, predictor variables and prevention opportuni-
ties among drug users in Italy. Journal of Viral Hepatitis, 2003, 10(5):394–400.
15. D’Oliveira A Jr et al. Prevalence and sexual risk of hepatitis C virus infection when human immunodefi-
ciency virus was acquired through sexual intercourse among patients of the Lyon University Hospitals,
France, 1992–2002. Journal of Viral Hepatitis, 2005, 12(3):330–332.
16. Chaix M-L et al. Homosexually transmitted HCV acute infection related to a clustered genotype 4
HCV in HIV-1-infected men and inefficacy of early antiviral therapy. In: Program and abstracts of the
12th Conference on Retroviruses and Opportunistic Infections. Boston, 22–25 February 2005 (Abstract
122).
17. Ackerman Z, Ackerman E, Paltiel O. Interfamilial transmission of hepatitis C virus: a systematic re-
view. Journal of Viral Hepatology, 2000, 7(2):93–103.
18. Jager J et al., eds. Hepatitis C and injecting drug use: impact, costs and policy options. Lisbon, Euro-
pean Monitoring Centre for Drugs and Drug Addiction, 2004 (EMCDDA Monographs).
19. Franciscus A. HCV Genotype and quasi-species. HCSPFACT Sheet. Hepatitis C Support Project, 2006
(http://www.hcvadvocate.org/hepatitis/factsheets_pdf/genotype_FS.pdf, accessed 28 February 2006).
20. Simmonds et al. Epidemiological, clinical and therapeutic associations of hepatitis C types in western
European patients. Journal of Hepatology, 1996, 24(5):517–524.
21. Zeuzem S et al. Risk factors for the transmission of hepatitis C. Journal of Hepatology, 1996, 24(2
Suppl.):3–10.
22. Salmon D et al. Therapeutic management of hepatitis and HIV infection in coinfected patients: results
of a survey performed before the 2005 Consensus Conference. Journal of Hepatology, 2006, 44(S1):
S2–S5.
23. Poynard T et al. A comparison of fibrosis progression in chronic liver diseases. Journal of Hepatology,
2003, 38:257–265.
268
Management of Hepatitis C and HIV Coinfection
24. Grebely J et al. Effect of HIV coinfection on spontaneous clearance of hepatitis C virus (HCV) in the
downtown Eastside of Vancouver. 3rd International AIDS Society Conference on HIV Pathogenesis and
Treatment, Rio de Janeiro, 24–27 July, 2005 (Abstract No. TuPe1.1C18).
25. Vallet-Pichard A, Pol S. Natural history and predictors of severity of chronic hepatitis C virus (HCV) and
human immunodeficiency virus (HIV) coinfection. Journal of Hepatology, 2006, 44(S1):S28–S34.
26. Benhamou Y et al. Liver fibrosis progression in HIV-HCV coinfected patients. The Multivirc Group.
Hepatology, 1999, 30:1054–1058.
27. Forns X, Costa J. HCV virological assessment. Journal of Hepatology, 2006, 44(S1):
S40–S43.
28. Thio CL et al. Screening for hepatitis C virus in human immunodeficiency virus-infected individuals.
Journal of Clinical Microbiology, 2000, 38(2):575–577.
29. Van Asten L, Prins M. Infection with concurrent multiple hepatitis C virus genotypes is associated with
faster HIV disease progression. AIDS, 2004, 18(17):2319–2324.
30. Nunez M, Soriano V. Hepatotoxicity of antiretrovirals: incidence, mechanisms and management. Drug
Safety, 2005, 28(1):53–66.
31. Pawlotsky JM. Use and interpretation of virological tests for hepatitis C. Hepatology, 2002, 36(5 Suppl.
1):S65–S73.
32. Thomas D. Options for treatment of hepatitis C in HIV-infected persons. Journal of Hepatology, 2006,
44(Suppl. 1):S40–S43.
33. Fried MW et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. The New
England Journal of Medicine, 2002, 347(13):975–982.
34. Torriani FJ et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-in-
fected patients. The New England Journal of Medicine, 2004, 351(5):438–450.
35. Leruez-Ville M et al. Large-scale analysis of hepatitis C virus serological typing assay: effectiveness
and limits. Journal of Medical Virology, 1998, 55(1):18–23.
36. Pugh RNH et al. Preoperative assessment of patients with liver disease. British Journal of Surgery,
1973, 60:646–649.
37. Bravo AA, Sheth SG, Chopra S. Liver biopsy. The New England Journal of Medicine, 2001, 344(7):495–
500.
38. Friedman SL. Score Metavir Evaluation of fibrosis and hepatitis C. American Journal of Medicine,
1999, 107(6B):27S–30S.
39. Kelleher TB, Afdha NL. Assessment of liver fibrosis in coinfected patients. Journal of Hepatology,
2006, 44(S1):S126–S131.
40. Nunes D et al. HIV infection does not affect the performance of non-invasive markers of
fibrosis for the diagnosis of hepatitis C virus-related liver disease. Journal of Acquired Immune Defi-
ciency Syndrome, 2005, 4(5):538–544).
41. Ce Ledinghen V et al. Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepa-
titis C virus-coinfected patients. Journal of Acquired Immune Deficiency Syndrome, 2006, 41(2):175–
179.
42. Nunes D et al. HIV infection does not affect the performance of non-invasive markers of
fibrosis for the diagnosis of hepatitis C virus-related liver disease. Journal of Acquired Immune Defi-
ciency Syndrome, 2005, 40(5):538–544.
43. Alberti A et al. Short statement of the first European Consensus Conference on the Treatment of Chron-
ic Hepatitis B and C in HIV Coinfected Patients. Journal of Hepatology, 2005, 42(5):615–624.
44. Hassan MM. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and
diabetes mellitus. Hepatology, 2002, 36:1206–1213.
45. Samet JH et al. A randomized controlled trial to enhance antiretroviral therapy adherence in patients
with a history of alcohol problems. Antiviral Therapy, 2005, 10(1):83–93.
46. European STD Guidelines. International Journal of STD & AIDS, 2001, 12(10) Supplement 3.
47. Mast EE et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history
of HCV infection acquired in infancy. Journal of Infectous Diseases, 2005, 192(11):1880–1889.
48. Kochhar DM, Penner JD, Knudsen TB. Embryotoxic, teratogenic, and metabolic effects of ribavirin in
mice. Toxicology and Applied Pharmacology, 1980, 52(1):99–112.
49. Hadziyannis SJ et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis
C: a randomized study of treatment duration and ribavirin dose. Annals of Internal Medicine, 2004,
140(5):346–355.
269
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
50. Marrache F et al. Safety and efficacy of peginterferon plus ribavirin in patients with chron-
ic hepatitis C and bridging fibrosis or cirrhosis. Journal of Viral Hepatology, 2005, 12(4):
421–428.
51. Vogel M et al. Treatment of acute hepatitis C infection in HIV-infected patients: a retrospective analysis
of eleven cases. Journal of Viral Hepatology, 2005, 12(2):207–211.
52. Sulkowski MS. Treatment algorithm for the management of hepatitis C in HIV-coinfected per-
sons. Journal of Hepatology, 2006, 44(Suppl.):S49–S55 (http://www.jhep-elsevier.com/article/PI-
ISO168827500735X/fulltext#, accessed 30 March 2006).
53. Perez-Olmeda M et al. Pegylated IFN-alpha2b plus ribavirin as therapy for chronic hepatitis C in HIV-
infected patients. AIDS, 2003, 17(7):1023–1028.
54. Scaling up antiretroviral therapy in resource-limited settings: treatment guidelines for a public health
approach: 2003 revision. Geneva, World Health Organization, 2004.
55. Patel SM et al. Serious adverse cutaneous and hepatic toxicities associated with nevirapine use by non-
HIV-infected individuals. Journal of Acquired Immune Deficiency Syndrome, 2004, 35(2):120–125.
56. Moreno A et al. High rate of didanosine-related mitochondrial toxicity in HIV-HCV coinfected patients
receiving didanosine. Antiviral Therapy, 2004, 9:133–138.
57. Salmon-Céron D et al. Mitochondrial toxic effects of ribavirin. The Lancet, 2001, 357:1803.
58. Lafeuillade A, Hittinger G, Chapadaud S. Increased mitochondrial toxicity with ribavirin in HIV-HCV
coinfection. The Lancet 2001, 357:280–281.
59. Mauss S. Risk factors for hepatic decompensation in patients with HIV/HCV coinfection and liver cir-
rhosis during interferon-based therapy. AIDS, 2004, 18(13):F21–25.
60. Rodriguez-Rosado R, Garcia-Samaniego J, Soriano V. Hepatotoxicity after introduction of highly ac-
tive antiretroviral therapy. AIDS, 1998, 12:1256.
61. Sulkowski MS et al. Hepatotoxicity associated with antiretroviral therapy in adults infected with human
immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA, 2000, 283:74–80.
62. Wit FW et al. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral com-
bination therapy. Journal of Infectious Diseases, 2002, 186:23–31.
63. Aceti A et al. Hepatotoxicity development during antiretroviral therapy containing protease
inhibitors in patients with HIV: the role of hepatitis B and C virus infection. Journal of Acquired Im-
mune Deficiency Syndrome, 2002, 29:41–48.
64. Torti C et al. Incidence and risk factors for liver enzyme elevation during highly active antiretroviral
therapy in HIV-HCV coinfected patients: results from the Italian EPOKA-MASTER Cohort. BMC In-
fectious Diseases, 2005, 5:58.
65. Wyles DL, Gerber JG. Antiretroviral drug pharmacokinetic in hepatitis with hepatic dysfunction. Clini-
cal Infectious Diseases, 2005, 40:174–181.
66. Salmon D, Taburet AM. Antiretroviral agents in HIV-infected patients with cirrhosis. Actuality on HIV
in 2005. La Presse médicale, 2005, 34, 10(Suppl. 1):S451–S52, 45.
67. Regazzi M et al. Clinical pharmacokinetics of nelfinavir and its metabolite M8 in human
immunodeficiency virus (HIV)-positive and HIV-hepatitis C virus-coinfected subjects. Antimicrobial
Agents and Chemotherapy, 2005, 49(2):643–649.
68. Arribas JR et al. Lopinavir/Ritonavir as single-drug therapy for maintenance of HIV-1 viral suppres-
sion: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK
study). Journal of Acquired Immune Deficiency Syndrome, 2005, 40(3):280–287.
69. Veronèse L et al. Single-dose pharmacokinetics of Amprenavir, a human Immunodeficiency Virus Type
1 protease inhibitor in subjects with normal or impaired hepatic function. Antimicrobial Agents and
Chemotherapy, 2002, 821–826.
70. Dominguez S et al. The HEPADOSE Study: evaluation of protease inhibitors and non-nucleoside
analogue plasma concentrations in HIV/HCV and HIV-infected patients. 3rd International AIDS So-
ciety Conference on HIV Pathogenesis and Treatment, Rio Janeiro, 24–27 July 2005 (Abstract No.
WePp0305; http://www.aegis.com/conferences/IASHIVPT/2005/WePp0305.pdf, accessed 28 February
2006).
71. Chutaputti A. Adverse effects and other safety aspects of the hepatitis C antivirals. Journal of Gastro-
enterology and Hepatology, 2000, 15(Suppl.E):156–163.
72. Sulkowski MS et al. Epoetin alfa once weekly improves anaemia in HIV/hepatitis C virus-coinfected
patients treated with interferon/ribavirin: a randomized controlled trial. Journal of Acquired Immune
Deficiency Syndrome, 2005, 39(4):504–506.
270
Management of Hepatitis C and HIV Coinfection
73. European Medicine Agency. Dosage adjustment of ribavirin Rebetol. London, 2006 (http://www.emea.
eu.int/humandocs/PDFs/EPAR/Rebetol/H-246-PI-en.pdf, accessed 28 February 2006).
74. European Medicine Agency. Dosage adjustment interferon Pegasys and Viraferon Peg. London, 2006
(http://www.emea.eu.int/humandocs/PDFs/EPAR/pegasys/H–395–PI–en.pdf and http://www.emea.
eu.int/humandocs/PDFs/EPAR/Viraferonpeg/H–329–PI–en.pdf, accessed 28 February 2006).
75. Moncoucy X et al. Risk factors and long-term course of thyroid dysfunction during antiviral treatments
in 221 patients with chronic hepatitis C. Gastroenterology and Clinical Biology, 2005, 29(4):339–345.
76. Puoti M et al. Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical
presentation and outcome. AIDS, 2004, 18(17):1–9.
77. Hoofnagle JH. Hepatocellular carcinoma: summary and recommendations. Gastroenterology, 2004,
127:S319–S323.
78. Samonakis DN et al. Management of portal hypertension. Postgraduate Medical Journal, 2004,
80(949):634–641.
79. Vogt MW et al. Ribavirin antagonizes the effect of azidothymidine on HIV replication.
Science, 1987, 235:1376–1379.
80. Sim SM et al. Effect of ribavirin on zidovudine efficacy and toxicity in vitro: a concentration-dependent
interaction. AIDS Research and Human Retroviruses, 1998, 14:1661–1667.
81. Salmon-Céron D et al. Interferon-ribavirin in association with stavudine has no impact on plasma hu-
man immunodeficiency virus (HIV) type 1 level in patients coinfected with HIV and hepatitis C virus:
a CORIST–ANRS HC1 trial. Clinical Infectious Diseases, 2003, 36:1295–1304.
82. Perronne C. Antiviral hepatitis and antiretroviral drug interactions. Journal of Hepatology, 2006, 44(S1):
S119–S125.
83. Baba M et al. Ribavirin antagonizes inhibitory effects of pyrimidine 2’,3’–dideoxynucleosides but en-
hances inhibitory effects of purine 2’, 3’– dideoxynucleosides on replication of human immunodefi-
ciency virus in vitro. Antimicrobial Agents and Chemotherapy, 1987, 31:1613–1617.
84. Hoggard PG, et al. Effects of drugs on 2’,3’–dideoxy–2’,3’–didehydrothymidine phosphorylation in
vitro. Antimicrobial Agents and Chemotherapy, 1997, 41:1231–1236.
85. Balzarini J et al. Mechanisms of the potentiating effect of ribavirin on the activity of 2’,3’–
dideoxyinosine against human immunodeficiency virus. Journal of Biological Chemistry, 1991,
266:21:509–514.
86. Harvie P et al. Ribavirin potentiates the efficacy and toxicity of 2’,3’–dideoxyinosine in the murine ac-
quired immunodeficiency syndrome model. Journal of Pharmacology and Experimental Therapeutics,
1996, 279:1009–1017.
87. Japour AJ et al. A phase-1 study of the safety, pharmacokinetics, and antiviral activity of
combination of didanosine and ribavirin in patients with HIV-1 disease. Journal of Acquired Immune
Deficiency Syndrome, 1996, 13:235–246.
88. Ungo JR et al. Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the hu-
man immunodeficiency virus. American Journal of Respiratory and Critical Care Medicine, 1998,
157(6 Pt 1):1871–1876.
89. Yee D et al. Incidence of serious side-effects from first-line antituberculosis drugs among patients
treated for active tuberculosis. American Journal of Respiratory and Critical Care Medicine, 2003,
167(11):1472–1477.
90. Hollingsworth RC et al. Serum HCV RNA levels assessed by quantitative NASBA: stability of viral
load over time, and lack of correlation with liver disease. The Trent HCV Study Group. Journal of
Hepatology, 1996, 25(3):301–306.
91. Forns X, Bukh J. Methods for determining the hepatitis C virus genotype. Viral Hepatitis
Reviews, 1998, 4:1–19.
92. Wai CT et al. A simple non-invasive index can predict both significant fibrosis and cirrhosis in patients
with chronic hepatitis C. Hepatology, 2003, 38(2):518–526.
93. Forns X et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predic-
tive model. Hepatology, 2002, 36(4 Pt 1):986–992.
94. Ziol M et al. Non-invasive assessment of liver fibrosis by measurement of stiffness in patients with
chronic hepatitis C. Hepatology, 2005, 41(1):48–54.
95. Imbert-Bismut F et al. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection:
a prospective study. The Lancet, 2001, 357(9262):1069–1075.
271
HIV/AIDS TREATMENT AND CARE CLINICAL PROTOCOLS FOR THE WHO EUROPEAN REGION
96. Castera L et al. Prospective comparison of transient elastography, Fibrotest, APRI and liv-
er biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology, 2005, 128(2):
343–350.
97. Patel K et al. Evaluation of a panel of non-invasive serum markers to differentiate mild from moder-
ate-to-advanced liver fibrosis in chronic hepatitis C patients. Journal of Hepatology, 2004, 41(6):935–
942.
98. Kelleher TB et al. Prediction of hepatic fibrosis in HIV/HCV coinfected patients using serum fibrosis
markers: the SHASTA index. Journal of Hepatology, 2005, 43(1):78–84.
99. Rosenberg WM et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterol-
ogy, 2004, 127(6):1704–1713.
100. Ewing JA. Detecting alcoholism: the CAGE questionnaire. JAMA, Journal of the American Medical
Association, 1984, 252:1905–1907.
101. Babor TF et al. AUDIT, the Alcohol Use Disorders Identification Test: guidelines for use in primary
care (2nd ed.). Geneva, World Health Organization, 2001 (http://whqlibdoc.who.int/hq/2001/WHO_
MSD_MSB_01.6a.pdf, accessed 29 March 2006).
102. Smukler AJ, Ratner L. Hepatitis viruses and hepatocellular carcinoma in HIV-infected
patients. Current Opinion in Oncology, 2002, 14:538–542.
103. Garcia-Samaniego J et al. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C.
American Journal of Gastroenterology, 2001, 96:179–183.
104. Davila JA et al. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a popu-
lation-based study. Gastroenterology, 2004, 127:1372–1380.
105. Bruix J et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000
EASL conference. European Association for the Study of the Liver. Journal of Hepatology, 2001,
3:421–430.
106. Daniele B et al. alpha-fetoprotein and ultrasonography screening for hepatocellular carcinoma. Gastro-
enterology, 2004, 127:S108–S112.
107. Samuel D et al. Liver transplantation in patients with HIV infection. Journal of Hepatology, 2003,
39(1):3–6.
108. Tzakis AG et al. Transplantation in HIV + patients. Transplantation, 1990, 49:354–358.
109. Miró JM et al. GESIDA/GESITRA-SEIMC, PNS and ONT consensus document on solid
organ transplant (SOT) in HIV-infected patients in Spain: March 2005. Enfermedades Infecciosas y
Microbiología Clínica, 2005, 23(6):353–362.
110. Ragni MV et al. Survival of human immunodeficiency virus-infected liver transplant recipients. Jour-
nal of Infectious Diseases, 2003, 188(10):1412–1420.
111. Bhopale GM, Nanda RK. Emerging drugs for chronic hepatitis C. Hepatology Research: the Official
Journal of the Japan Society of Hepatology, 2005, 32(3):146–153.
112. De Francesco R, Migliaccio G. Challenges and successes in developing new therapies for hepatitis C.
Nature, 2005, 436(18):953–960.
272